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Intratumoral estrogen sulfotransferase induction contributes to the anti-breast cancer effects of the dithiocarbamate derivative TM208
Ji, Xi-wei1,2; Chen, Guang-ping4; Song, Yan5; Hua, Ming1; Wang, Li-jie1; Li, Liang1; Yuan, Yin1; Wang, Si-yuan1; Zhou, Tian-yan1,3; Lu, Wei1,3
关键词Breast Cancer Dithiocarbamate Tamoxifen Estrogen Estrogen Sulfotransferase Human Tumor Xenograft Model Uterotropic Bioassay
刊名ACTA PHARMACOLOGICA SINICA
2015-10-01
DOI10.1038/aps.2015.14
36期:10页:1246-1255
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Chemistry, Multidisciplinary ; Pharmacology & Pharmacy
研究领域[WOS]Chemistry ; Pharmacology & Pharmacy
关键词[WOS]Steroid-producing Enzymes ; Cytosolic Sulfotransferases ; Aromatase Activities ; Sex Steroids ; In-situ ; Expression ; Tamoxifen ; Cells ; Liver ; Carcinoma
英文摘要

Aim: Sulfotransferase-catalyzed sulfation is the most important pathway for inactivating estrogens. Thus, activation of estrogen sulfotransferase (EST) may be an alternative approach for the treatment of estrogen-dependent breast cancer. In this study we investigated the involvement of EST in anti-breast cancer effects of the dithiocarbamate derivative TM208 in vitro and in vivo.

Methods: The viability of human breast cancer MCF-7 cells was determined using a SBB assay. Nude mice bearing MCF-7 cells were orally administered TM208 (50 and 150 mg.kg(-1).d(-1)) for 18 days. The xenograft tumors and uteri were collected. The mRNA expression of EST was examined with real-time PCR. EST protein was detected with Western blot, ELISA or immunohistochemical staining assays. A radioactive assay was used to measure the EST activity. Uterotropic bioassay was used to examine the uterine estrogen responses.

Results: Treatment with TM208 (10, 15 and 20 mu mol/L) concentration-dependently increased EST expression in MCF-7 cells in vitro. Co-treatment with triclosan, an inhibitor of sulfonation, abolished TM208-induced cytotoxicity in MCF-7 cells. TM208 exhibited an apparent anti-estrogenic property: it exerted more potent cytotoxicity in E2-treated MCF-7 cells. In the nude mice bearing MCF-7 cells, TM208 administration time-dependently increased the expression and activity of EST, and blocked the gradual increase of E2 concentration in the xenograft tumors. Furthermore, TM208 administration blocked the estrogens-stimulated uterine enlargement. Tamoxifen, a positive control drug, produced similar effects on the expression and activity of EST in vitro and in vivo.

Conclusion: The induction of EST and reduction of estrogen concentration contribute to the anti-breast cancer action of TM208 and tamoxifen. TM208 may be developed as anticancer drug for the treatment of estrogen receptor-positive breast cancer.

语种英语
WOS记录号WOS:000362459200011
通讯作者邮箱tianyanzhou@bjmu.edu.cn
项目编号81273583
资助机构National Natural Science Foundation of China (NSFC)
引用统计
被引频次:3[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
版本出版稿
条目标识符http://ir.bjmu.edu.cn/handle/400002259/61444
专题北京大学药学院_分子与细胞药理学系
北京大学药学院_药剂学系
作者单位1.Peking Univ, Sch Pharmaceut Sci, Dept Pharmaceut, Beijing 100191, Peoples R China
2.Peking Univ, Hosp 1, Inst Clin Pharmacol, Beijing 100191, Peoples R China
3.Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
4.Oklahoma State Univ, Ctr Vet Hlth Sci, Dept Physiol Sci, Stillwater, OK 74078 USA
5.Peking Univ, Sch Pharmaceut Sci, Dept Mol & Cellular Pharmacol, Beijing 100191, Peoples R China
推荐引用方式
GB/T 7714
Ji, Xi-wei,Chen, Guang-ping,Song, Yan,et al. Intratumoral estrogen sulfotransferase induction contributes to the anti-breast cancer effects of the dithiocarbamate derivative TM208[J]. ACTA PHARMACOLOGICA SINICA,2015,36(10):1246-1255.
APA Ji, Xi-wei.,Chen, Guang-ping.,Song, Yan.,Hua, Ming.,Wang, Li-jie.,...&Lu, Wei.(2015).Intratumoral estrogen sulfotransferase induction contributes to the anti-breast cancer effects of the dithiocarbamate derivative TM208.ACTA PHARMACOLOGICA SINICA,36(10),1246-1255.
MLA Ji, Xi-wei,et al."Intratumoral estrogen sulfotransferase induction contributes to the anti-breast cancer effects of the dithiocarbamate derivative TM208".ACTA PHARMACOLOGICA SINICA 36.10(2015):1246-1255.
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